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Robert Clarke - One of the best experts on this subject based on the ideXlab platform.
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nf κb signaling is required for xbp1 unspliced and spliced mediated effects on Antiestrogen responsiveness and cell fate decisions in breast cancer
Molecular and Cellular Biology, 2015Co-Authors: Anni Warri, Rebecca B. Riggins, Lu Jin, Alan Zwart, Hongbin Fang, Robert ClarkeAbstract:Antiestrogen therapy induces the unfolded protein response (UPR) in estrogen receptor-positive (ER(+)) breast cancer. X-box binding protein 1 (XBP1), which exists in the transcriptionally inactive unspliced form [XBP1(U)] and the spliced active form [XBP1(S)], is a key UPR component mediating Antiestrogen resistance. We now show a direct link between the XBP1 and NF-κB survival pathways in driving the cell fate decisions in response to Antiestrogens in ER(+) breast cancer cells, both in vitro and in a xenograft mouse model. Using novel spliced and nonspliceable forms of XBP1, we show that XBP1(U) functions beyond being a dominant negative of XBP1(S). Both isoforms regulate NF-κB activity via ERα; XBP1(S) is more potent because it also directly regulates p65/RelA expression. These findings provide new insights into the fundamental signaling activities of spliced and unspliced XBP1 in breast cancer, establish NF-κB to be a mediator of these activities, and identify XBP1 and its splicing to be novel therapeutic targets.
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abstract 679 glutamine metabolism in myc driven Antiestrogen resistant breast cancer cells confers metabolic flexibility through the unfolded protein response
Cancer Research, 2014Co-Authors: Ayesha N Shajahanhaq, Katherine L Cook, Jessica L Schwartzroberts, Anni Warri, Ahreej E Eltayeb, Diane M Demas, Leena Hilakiviclarke, Robert ClarkeAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Antiestrogens are used to treat estrogen receptor positive (ER+) breast tumors that constitute 70% of all breast cancer cases. Unfortunately, acquired resistance to Antiestrogen therapy remains a critical clinical obstacle. Here we show that human breast cancer cells and rat mammary tumors that have acquired resistance to Antiestrogens express increased levels of MYC, a major regulator of both glutamine and glucose. Glutamine metabolism and glucose uptake were elevated in ER+ Antiestrogen resistant cells (LCC9) compared with sensitive cells (LCC1). Inhibition of MYC, with siRNA or small molecule inhibitor, reduced cell viability and uptake of both glutamine and glucose in resistant cells. In resistant cells, MYC expression controlled protein levels of glutamine, glutamate and glucose transporters as well as GLUL and GLS, two enzymes that promote glutamate-glutamine inter-conversion. Increased MYC function in resistant cells correlated with increased cellular sensitivity to deprivation of, and also inhibitors of, both glutamine and glucose. While apoptosis eliminated all resistant cells in glucose-only conditions beyond 72 h, in glutamine-only conditions, the unfolded protein response (UPR) via GRP78-IRE1α and activating JNK and increased CHOP, induced apoptosis in majority of the cells but promoted survival in some. The Antiestrogen faslodex (FAS; ICI 182,780) significantly reduced glucose uptake in Antiestrogen resistant cells compared with sensitive cells. Thus, our findings reveal unique roles for MYC in promoting metabolic flexibility in and promoting survival in Antiestrogen resistant breast cancer cells via the UPR. Targeting glutamine and glucose metabolism pathways, therefore, may provide novel strategies in treating endocrine resistant breast cancers. Citation Format: Ayesha N. Shajahan-Haq, Katherine L. Cook, Jessica L. Schwartz-Roberts, Ahreej E. Eltayeb, Diane M. Demas, Anni M. Warri, Leena A. Hilakivi-Clarke, Robert Clarke. Glutamine metabolism in MYC-driven Antiestrogen resistant breast cancer cells confers metabolic flexibility through the unfolded protein response. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 679. doi:10.1158/1538-7445.AM2014-679
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knockdown of estrogen receptor α induces autophagy and inhibits Antiestrogen mediated unfolded protein response activation promoting ros induced breast cancer cell death
The FASEB Journal, 2014Co-Authors: Katherine L Cook, Pamela A G Clarke, Jignesh H Parmar, Jessica L Schwartzroberts, Mones Abuasab, Anni Warri, William T Baumann, Robert ClarkeAbstract:Approximately 70% of all newly diagnosed breast cancers express estrogen receptor (ER)-α. Although inhibiting ER action using targeted therapies such as fulvestrant (ICI) is often effective, later emergence of Antiestrogen resistance limits clinical use. We used Antiestrogen-sensitive and -resistant cells to determine the effect of Antiestrogens/ERα on regulating autophagy and unfolded protein response (UPR) signaling. Knockdown of ERα significantly increased the sensitivity of LCC1 cells (sensitive) and also resensitized LCC9 cells (resistant) to Antiestrogen drugs. Interestingly, ERα knockdown, but not ICI, reduced nuclear factor (erythroid-derived 2)-like (NRF)-2 (UPR-induced antioxidant protein) and increased cytosolic kelch-like ECH-associated protein (KEAP)-1 (NRF2 inhibitor), consistent with the observed increase in ROS production. Furthermore, autophagy induction by Antiestrogens was prosurvival but did not prevent ERα knockdown–mediated death. We built a novel mathematical model to elucidate the ...
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Targeting GRP78 and Antiestrogen resistance in breast cancer.
Future medicinal chemistry, 2013Co-Authors: Katherine L Cook, Pamela A G Clarke, Robert ClarkeAbstract:Faslodex ® often fail to cure these patients. Many estrogen receptor-positive tumors lose drug sensitivity, making endocrine resistance a major clinical problem. Recently, investigation into the molecular mechanisms of endocrine resistance has highlighted a causative role of the unfolded protein response in Antiestrogen resistance. In particular, the master regulator of the unfolded protein response, GRP78, was observed to be elevated in endocrine-resistant breast cancer and directly affected Antiestrogen therapy responsiveness. GRP78 was found to impact many different cellular processes that may affect breast cancer survival. Recently, various compounds have been reported to affect GRP78 activity and it may be advantageous to combine these drugs with Antiestrogens to overcome endocrine therapy resistance.
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abstract 2266 beclin 1 regulation of autophagy in endocrine resistant breast cancer
Cancer Research, 2012Co-Authors: Caroline O B Facey, Ayesha N Shajahan, Robert ClarkeAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Resistance to endocrine therapy occurs in nearly 50% of all patients diagnosed with estrogen receptor ≤ positive breast cancer, thus elucidating mechanism(s) of endocrine resistance is of major importance. To provide a model, we selected MCF7 variants that are estrogen independent and either sensitive (LCC1) or resistant (LCC9) to Antiestrogens: Faslodex (FAS; ICI 182, 780) and Tamoxifen (TAM). Antiestrogens induce endoplasmic reticulum stress which, depending on cell type, stimulus, and duration, may subsequently activate the unfolded protein response (UPR), autophagy, and/or apoptosis. Gene microarray analysis of LCC9 cells show high expression levels of X-box binding protein 1 (XBP1), implicating the unfolded protein response (UPR) as a pro-survival mechanism of resistance. In addition to an elevated UPR, autophagy is substantially elevated in response to Antiestrogens. To better understand the role of autophagy in Antiestrogen responsiveness, we investigated the consequence of knocking down BECLIN-1 in LCC1 and LCC9 cells treated with FAS and TAM. Preliminary results indicate a time-dependent change in autophagy following knock-down of beclin-1 in response to short-term (48h) and long-term (6 day) treatment. At 48h, sensitive LCC1 cells respond to Antiestrogens with high levels of autophagy measured by increased LC3BII to LC3BI ratio and decreased expression of p62. Relative cell density (measured by crystal violet assay) decreases by 20% at 48h and by 80% at 6 days in LCC1 cells however, LCC9 cells are minimally affected by Antiestrogen treatment. The level of autophagy remains high at 6 days in sensitive cells however levels remain constant in resistant cells. Autophagy is significantly lowered by reduced BECN1 in both sensitive and resistant cells however there is an increase in cell density in sensitive cells transfected with BECN1- shRNA at 6 days, indicating an autophagy associated programmed cell death mechanism in response to Antiestrogen treatment. Protein expression of an active form of caspase −12/4 (an initiator caspase activated during endoplasmic reticulum stress) is elevated in sensitive cells at 6 days in response to Antiestrogen treatment, also indicating the onset of apoptosis at this time. Elevated expression of Bcl-2 family members in resistant cells may play a more substantial role than BECN1 alone, as the combination of Bcl-2 family protein inhibitors and BECN1-shRNA sensitizes resistant cells to a greater extent. Thus, Bcl-2 family members in resistant cells may play a critical role in managing the balance between cell survival (moderate autophagy) and programmed cell death (excessive autophagy and apoptosis) in response to Antiestrogen treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2266. doi:1538-7445.AM2012-2266
Claude Labrie - One of the best experts on this subject based on the ideXlab platform.
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comparison of the effects of em 652 sch57068 tamoxifen toremifene droloxifene idoxifene gw 5638 and raloxifene on the growth of human zr 75 1 breast tumors in nude mice
International Journal of Cancer, 2002Co-Authors: Matthieu Gutman, Steeve Couillard, Jenny Roy, Fernand Labrie, Bernard Candas, Claude LabrieAbstract:EM-652 exerts pure Antiestrogenic activity in the mammary gland and endometrium, while tamoxifen, the Antiestrogen most widely used for the treatment of breast cancer, exerts mixed Antiestrogenic-estrogenic activity in these tissues. Our objective was to compare the agonistic and antagonistic effects of EM-652 with tamoxifen and 5 other Antiestrogens on the growth of ZR-75-1 human breast xenografts in ovariectomized nude mice. During the 23 weeks of treatment at a daily oral dose of 50 microg, EM-652 was the only compound that decreased tumor size relative to pretreatment values, whereas the 6 other Antiestrogens only decreased to various extents the progression rate stimulated by estrone. Under estrone stimulation, all groups of animals had more than 60% of their tumors in the progression category except for the EM-652-treated group, where only 7% of the tumors progressed. In the absence of estrone stimulation, progression was seen in 60%, 33%, 21% and 12% of tumors in the tamoxifen-, idoxifene-, toremifene- and raloxifene-treated groups, respectively, while only 4% of tumors progressed in the EM-652-treated group. The agonistic and antagonistic actions of each Antiestrogen were also measured on endometrial epithelial cell thickness. Our present findings indicate that EM-652, in addition to being the most potent Antiestrogen on human breast tumor growth, has no agonistic effect in breast and endometrial tissues. Since previous data have shown benefits of EM-652 on bone density and lipid profile, this compound could be an ideal candidate for chemoprevention of breast and uterine cancers, while protecting against osteoporosis and cardiovascular disease.
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comparison of the effects of em 652 sch57068 tamoxifen toremifene droloxifene idoxifene gw 5638 and raloxifene on the growth of human zr 75 1 breast tumors in nude mice
International Journal of Cancer, 2002Co-Authors: Matthieu Gutman, Steeve Couillard, Fernand Labrie, Bernard Candas, Claude LabrieAbstract:EM-652 exerts pure Antiestrogenic activity in the mammary gland and endometrium, while tamoxifen, the Antiestrogen most widely used for the treatment of breast cancer, exerts mixed Antiestrogenic–estrogenic activity in these tissues. Our objective was to compare the agonistic and antagonistic effects of EM-652 with tamoxifen and 5 other Antiestrogens on the growth of ZR-75-1 human breast xenografts in ovariectomized nude mice. During the 23 weeks of treatment at a daily oral dose of 50 μg, EM-652 was the only compound that decreased tumor size relative to pretreatment values, whereas the 6 other Antiestrogens only decreased to various extents the progression rate stimulated by estrone. Under estrone stimulation, all groups of animals had more than 60% of their tumors in the progression category except for the EM-652–treated group, where only 7% of the tumors progressed. In the absence of estrone stimulation, progression was seen in 60%, 33%, 21% and 12% of tumors in the tamoxifen-, idoxifene-, toremifene- and raloxifene-treated groups, respectively, while only 4% of tumors progressed in the EM-652–treated group. The agonistic and antagonistic actions of each Antiestrogen were also measured on endometrial epithelial cell thickness. Our present findings indicate that EM-652, in addition to being the most potent Antiestrogen on human breast tumor growth, has no agonistic effect in breast and endometrial tissues. Since previous data have shown benefits of EM-652 on bone density and lipid profile, this compound could be an ideal candidate for chemoprevention of breast and uterine cancers, while protecting against osteoporosis and cardiovascular disease. © 2002 Wiley-Liss, Inc.
Benita S. Katzenellenbogen - One of the best experts on this subject based on the ideXlab platform.
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estrogen receptor alpha somatic mutations y537s and d538g confer breast cancer endocrine resistance by stabilizing the activating function 2 binding conformation
eLife, 2016Co-Authors: Sean W Fanning, Christopher G Mayne, Venkatasubramanian Dharmarajan, Kathryn E Carlson, Teresa A Martin, Scott J Novick, Weiyi Toy, B D Green, Srinivas Panchamukhi, Benita S. KatzenellenbogenAbstract:Around one in every eight women will be diagnosed with breast cancer in their lifetime. Hormone-based therapies – also referred to Antiestrogen drugs – target a protein called estrogen receptor alpha and are effective treatments for the majority of these cancers. Unfortunately, about half of patients will develop recurrent breast cancers even though the cancer continues to produce the target of the drugs. The estrogen receptor alpha drives breast cancer in a number of ways, many of which require the receptor to be activated by binding to the hormone estrogen. When estrogen binds it causes the receptor to change shape to expose a surface where other proteins called coactivators can bind. Once a coactivator is bound, the estrogen receptor is active and signals the cancer cell to grow, divide, invade local tissues, and spread to new sites in the body. Antiestrogen drugs competitively block the binding of estrogen to the receptor and cause the receptor to take on a different shape that inhibits the binding of the coactivator. However, recent studies identified mutations at specific sites in the gene that encodes estrogen receptor alpha in a large subset of patients with breast cancers that have spread. These mutations make the receptor resistant to Antiestrogen drugs, and two mutations (called Y537S and D538G) account for approximately 70% of cases. However, it was not clear how these mutations altered the activity of estrogen receptor alpha at the molecular level. Fanning, Mayne, Dharmarajan et al. now show these two most common mutations allow estrogen receptor alpha to bind to the coactivator in the absence of hormone. This unfortunately also reduces the effectiveness of one of the mostly widely administered Antiestrogen therapies – a drug called tamoxifen. However, Fanning, Mayne, Dharmarajan et al. also show that the newer and more potent Antiestrogens that are currently under examination in clinical trials should be highly effective at treating the cancers with the mutated versions of estrogen receptor alpha. Applying the knowledge gained from these new findings toward the development of new Antiestrogens could help reverse the impact of these common mutations. If successful, these new drugs will provide life-saving treatments for many breast cancer patients.
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Antiestrogens: Mechanisms of action and resistance in breast cancer
Breast Cancer Research and Treatment, 1997Co-Authors: Benita S. Katzenellenbogen, Monica M. Montano, Kirk Ekena, Mary E. Herman, Eileen M. McinerneyAbstract:Antiestrogens have proven to be highly effective in the treatment of hormone-responsive breast cancer. However, resistance to Antiestrogen therapy often develops. In addition, although tamoxifen-like Antiestrogens are largely inhibitory and function as estrogen antagonists in breast cancer cells, they also have some estrogen-like activity in other cells of the body. Thus, recent efforts are being directed toward the development of even more tissue-selective Antiestrogens, i.e. compounds that are Antiestrogenic on breast and uterus while maintaining the beneficial estrogen-like actions on bone and the cardiovascular system. Efforts are also being directed toward understanding ligand structure-estrogen receptor (ER) activity relationships and characterizing the molecular changes that underlie alterations in parallel signal transduction pathways that impact on the ER. Recent findings show that Antiestrogens, which are known to exert most of their effects through the ER of breast cancer cells, contact a different set of amino acids in the hormone binding domain of the ER than those contacted by estrogen, and evoke a different receptor conformation that results in reduced or no transcriptional activity on most genes. Resistance to Antiestrogen therapy may develop due to changes at the level of the ER itself, and at pre- and post-receptor points in the estrogen receptor-response pathway. Resistance could arise in at least four ways: (1) ER loss or mutation; (2) Post-receptor alterations including changes in cAMP and phosphorylation pathways, or changes in coregulator and transcription factor interactions that affect the transcriptional activity of the ER; (3) Changes in growth factor production/sensitivity or paracrine cell-cell interactions; or (4) Pharmacological changes in the Antiestrogen itself, including altered uptake and retention or metabolism of the Antiestrogen. Model cell systems have been developed to study changes that accompany and define the Antiestrogen resistant versus sensitive breast cancer phenotype. This information should lead to the development of Antiestrogens with optimized tissue selectivity and agents to which resistance may develop more slowly. In addition, Antiestrogens which work through somewhat different mechanisms of interaction with the ER should prove useful in treatment of some breast cancers that become resistant to a different category of Antiestrogens.
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Antiestrogens: Mechanisms of action and resistance in breast cancer
Breast cancer research and treatment, 1997Co-Authors: Benita S. Katzenellenbogen, Monica M. Montano, Kirk Ekena, Mary E. Herman, Eileen M. McinerneyAbstract:Antiestrogens have proven to be highly effective in the treatment of hormone-responsive breast cancer. However, resistance to Antiestrogen therapy often develops. In addition, although tamoxifen-like Antiestrogens are largely inhibitory and function as estrogen antagonists in breast cancer cells, they also have some estrogen-like activity in other cells of the body. Thus, recent efforts are being directed toward the development of even more tissue-selective Antiestrogens, i.e. compounds that are Antiestrogenic on breast and uterus while maintaining the beneficial estrogen-like actions on bone and the cardiovascular system. Efforts are also being directed toward understanding ligand structure-estrogen receptor (ER) activity relationships and characterizing the molecular changes that underlie alterations in parallel signal transduction pathways that impact on the ER. Recent findings show that Antiestrogens, which are known to exert most of their effects through the ER of breast cancer cells, contact a different set of amino acids in the hormone binding domain of the ER than those contacted by estrogen, and evoke a different receptor conformation that results in reduced or no transcriptional activity on most genes.
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different regions in activation function 1 of the human estrogen receptor required for Antiestrogen and estradiol dependent transcription activation
Journal of Biological Chemistry, 1996Co-Authors: Eileen M. Mcinerney, Benita S. KatzenellenbogenAbstract:Abstract The human estrogen receptor (ER) is a ligand-inducible transcription factor that contains two transcriptional activation functions, one located in the NH2-terminal region of the protein (AF-1) and the second in the COOH-terminal region (AF-2). Antiestrogens, such as trans-hydroxytamoxifen (TOT), have partial agonistic activity in certain cell types, and studies have implied that this agonism is AF-1-dependent. We have made progressive NH2-terminal and other segment deletions and ligations in the A/B domain, and studied the transcriptional activity of these mutant ERs in ER-negative MDA-MB-231 human breast cancer and HEC-1 human endometrial cancer cells. Using several estrogens and several partial agonist/antagonist Antiestrogens, we find that estrogens and Antiestrogens require different regions of AF-1 for transcriptional activation. Deletion of the first 40 amino acids has no effect on receptor activity. Antiestrogen agonism is lost upon deletion to amino acid 87, while estrogen agonism is not lost until deletions progress to amino acid 109. Antiestrogen agonism has been further defined to require amino acids 41-64, as deletion of only these amino acids results in an ER that exhibits 100% activity with E2, but no longer shows an agonist response to TOT. With A/B-modified receptors in which Antiestrogens lose their agonistic activity, the Antiestrogens then function as pure estrogen antagonists. Our studies show that in these cellular contexts, hormone-dependent transcription utilizes a range of the amino acid sequence within the A/B domain. Furthermore, the agonist/antagonist balance and activity of Antiestrogens such as TOT are determined by specific sequences within the A/B domain and thus may be influenced by differences in levels of specific factors that interact with these regions of the ER.
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Human estrogen receptor ligand activity inversion mutants: receptors that interpret Antiestrogens as estrogens and estrogens as Antiestrogens and discriminate among different Antiestrogens
Molecular endocrinology (Baltimore Md.), 1996Co-Authors: Monica M. Montano, Kirk Ekena, Kristopher D. Krueger, Anne L. Keller, Benita S. KatzenellenbogenAbstract:The estrogen receptor (ER) is a transcription factor whose activity is normally activated by the hormone estradiol and inhibited by Antiestrogen. It has been found that certain mutational changes in the activation function-2 region in the hormone-binding domain of the human ER result in ligand activity inversion mutants, i.e. receptors that are now activated by Antiestrogen and inhibited by estrogen. The ER point mutant L540Q is activated by several Antiestrogens (the more pure Antiestrogens ICI 164,384 and RU 54,876 or the partial Antiestrogen trans-hydroxytamoxifen) but not by estradiol. The presence of the F domain and an intact activation function-i in the A/B domain are required for this activity, as is the DNA-binding ability of the receptor. This inverted ligand activity is observed with several estrogen-responsive promoters, both simple and complex; however, the activating ability of Antiestrogens is observed only in some cells, highlighting the important role of cell-specific factors in ligand interpretation. The introduction of two additional amino acid changes close to 540 results in receptors that are still not activated by estradiol but are now able to distinguish between partial Antiestrogens (which remain agonistic) and pure Antiestrogens (which show a greatly reduced stimulatory activity). These ligand activity inversion mutants remain stable in cells in the presence of the Antiestrogen ICI 164,384, as does a related ER mutant receptor that shows the normal, wild type ER ligand activity profile in which ICI 164,384 is transcriptionally inactive. Thus, the presence of adequate levels of mutant ER may be necessary but not sufficient for ICI 164,384 to elicit transcriptional activity. These findings highlight the means by which the carboxyl-terminal region in domain E functions to interpret the activity of a ligand, and they demonstrate that rather minimal changes in the ER can result in receptors with inverted response to Antiestrogen and estrogen. Such point mutations, if present in estrogen target cells, would result in Antiestrogens being seen as growth stimulators, rather than suppressors, with potentially detrimental consequences in terms of breast cancer treatment with Antiestrogens.
Matthieu Gutman - One of the best experts on this subject based on the ideXlab platform.
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comparison of the effects of em 652 sch57068 tamoxifen toremifene droloxifene idoxifene gw 5638 and raloxifene on the growth of human zr 75 1 breast tumors in nude mice
International Journal of Cancer, 2002Co-Authors: Matthieu Gutman, Steeve Couillard, Jenny Roy, Fernand Labrie, Bernard Candas, Claude LabrieAbstract:EM-652 exerts pure Antiestrogenic activity in the mammary gland and endometrium, while tamoxifen, the Antiestrogen most widely used for the treatment of breast cancer, exerts mixed Antiestrogenic-estrogenic activity in these tissues. Our objective was to compare the agonistic and antagonistic effects of EM-652 with tamoxifen and 5 other Antiestrogens on the growth of ZR-75-1 human breast xenografts in ovariectomized nude mice. During the 23 weeks of treatment at a daily oral dose of 50 microg, EM-652 was the only compound that decreased tumor size relative to pretreatment values, whereas the 6 other Antiestrogens only decreased to various extents the progression rate stimulated by estrone. Under estrone stimulation, all groups of animals had more than 60% of their tumors in the progression category except for the EM-652-treated group, where only 7% of the tumors progressed. In the absence of estrone stimulation, progression was seen in 60%, 33%, 21% and 12% of tumors in the tamoxifen-, idoxifene-, toremifene- and raloxifene-treated groups, respectively, while only 4% of tumors progressed in the EM-652-treated group. The agonistic and antagonistic actions of each Antiestrogen were also measured on endometrial epithelial cell thickness. Our present findings indicate that EM-652, in addition to being the most potent Antiestrogen on human breast tumor growth, has no agonistic effect in breast and endometrial tissues. Since previous data have shown benefits of EM-652 on bone density and lipid profile, this compound could be an ideal candidate for chemoprevention of breast and uterine cancers, while protecting against osteoporosis and cardiovascular disease.
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comparison of the effects of em 652 sch57068 tamoxifen toremifene droloxifene idoxifene gw 5638 and raloxifene on the growth of human zr 75 1 breast tumors in nude mice
International Journal of Cancer, 2002Co-Authors: Matthieu Gutman, Steeve Couillard, Fernand Labrie, Bernard Candas, Claude LabrieAbstract:EM-652 exerts pure Antiestrogenic activity in the mammary gland and endometrium, while tamoxifen, the Antiestrogen most widely used for the treatment of breast cancer, exerts mixed Antiestrogenic–estrogenic activity in these tissues. Our objective was to compare the agonistic and antagonistic effects of EM-652 with tamoxifen and 5 other Antiestrogens on the growth of ZR-75-1 human breast xenografts in ovariectomized nude mice. During the 23 weeks of treatment at a daily oral dose of 50 μg, EM-652 was the only compound that decreased tumor size relative to pretreatment values, whereas the 6 other Antiestrogens only decreased to various extents the progression rate stimulated by estrone. Under estrone stimulation, all groups of animals had more than 60% of their tumors in the progression category except for the EM-652–treated group, where only 7% of the tumors progressed. In the absence of estrone stimulation, progression was seen in 60%, 33%, 21% and 12% of tumors in the tamoxifen-, idoxifene-, toremifene- and raloxifene-treated groups, respectively, while only 4% of tumors progressed in the EM-652–treated group. The agonistic and antagonistic actions of each Antiestrogen were also measured on endometrial epithelial cell thickness. Our present findings indicate that EM-652, in addition to being the most potent Antiestrogen on human breast tumor growth, has no agonistic effect in breast and endometrial tissues. Since previous data have shown benefits of EM-652 on bone density and lipid profile, this compound could be an ideal candidate for chemoprevention of breast and uterine cancers, while protecting against osteoporosis and cardiovascular disease. © 2002 Wiley-Liss, Inc.
Steeve Couillard - One of the best experts on this subject based on the ideXlab platform.
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comparison of the effects of em 652 sch57068 tamoxifen toremifene droloxifene idoxifene gw 5638 and raloxifene on the growth of human zr 75 1 breast tumors in nude mice
International Journal of Cancer, 2002Co-Authors: Matthieu Gutman, Steeve Couillard, Jenny Roy, Fernand Labrie, Bernard Candas, Claude LabrieAbstract:EM-652 exerts pure Antiestrogenic activity in the mammary gland and endometrium, while tamoxifen, the Antiestrogen most widely used for the treatment of breast cancer, exerts mixed Antiestrogenic-estrogenic activity in these tissues. Our objective was to compare the agonistic and antagonistic effects of EM-652 with tamoxifen and 5 other Antiestrogens on the growth of ZR-75-1 human breast xenografts in ovariectomized nude mice. During the 23 weeks of treatment at a daily oral dose of 50 microg, EM-652 was the only compound that decreased tumor size relative to pretreatment values, whereas the 6 other Antiestrogens only decreased to various extents the progression rate stimulated by estrone. Under estrone stimulation, all groups of animals had more than 60% of their tumors in the progression category except for the EM-652-treated group, where only 7% of the tumors progressed. In the absence of estrone stimulation, progression was seen in 60%, 33%, 21% and 12% of tumors in the tamoxifen-, idoxifene-, toremifene- and raloxifene-treated groups, respectively, while only 4% of tumors progressed in the EM-652-treated group. The agonistic and antagonistic actions of each Antiestrogen were also measured on endometrial epithelial cell thickness. Our present findings indicate that EM-652, in addition to being the most potent Antiestrogen on human breast tumor growth, has no agonistic effect in breast and endometrial tissues. Since previous data have shown benefits of EM-652 on bone density and lipid profile, this compound could be an ideal candidate for chemoprevention of breast and uterine cancers, while protecting against osteoporosis and cardiovascular disease.
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comparison of the effects of em 652 sch57068 tamoxifen toremifene droloxifene idoxifene gw 5638 and raloxifene on the growth of human zr 75 1 breast tumors in nude mice
International Journal of Cancer, 2002Co-Authors: Matthieu Gutman, Steeve Couillard, Fernand Labrie, Bernard Candas, Claude LabrieAbstract:EM-652 exerts pure Antiestrogenic activity in the mammary gland and endometrium, while tamoxifen, the Antiestrogen most widely used for the treatment of breast cancer, exerts mixed Antiestrogenic–estrogenic activity in these tissues. Our objective was to compare the agonistic and antagonistic effects of EM-652 with tamoxifen and 5 other Antiestrogens on the growth of ZR-75-1 human breast xenografts in ovariectomized nude mice. During the 23 weeks of treatment at a daily oral dose of 50 μg, EM-652 was the only compound that decreased tumor size relative to pretreatment values, whereas the 6 other Antiestrogens only decreased to various extents the progression rate stimulated by estrone. Under estrone stimulation, all groups of animals had more than 60% of their tumors in the progression category except for the EM-652–treated group, where only 7% of the tumors progressed. In the absence of estrone stimulation, progression was seen in 60%, 33%, 21% and 12% of tumors in the tamoxifen-, idoxifene-, toremifene- and raloxifene-treated groups, respectively, while only 4% of tumors progressed in the EM-652–treated group. The agonistic and antagonistic actions of each Antiestrogen were also measured on endometrial epithelial cell thickness. Our present findings indicate that EM-652, in addition to being the most potent Antiestrogen on human breast tumor growth, has no agonistic effect in breast and endometrial tissues. Since previous data have shown benefits of EM-652 on bone density and lipid profile, this compound could be an ideal candidate for chemoprevention of breast and uterine cancers, while protecting against osteoporosis and cardiovascular disease. © 2002 Wiley-Liss, Inc.